Targeted Chronic Myeloid Leukemia Therapy: Seeking a Cure

BACKGROUND: Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer driven by the BCr-ABL fusion protein that arises from the translocation of chromosomes 9 and 22. The disease begins with an indolent chronic phase (CP) that can last for 3 to 5 years. If untreated, it progresses into accelerated phase (AP) and within a year, blast phase (BP). Survival at this point is less than 1 year. During disease progression, mutations and the Philadelphia chromosome (Ph) appear (a process called clonal evolution). The only known curative therapy for CML is allogeneic bone marrow transplant (BMT). However, toxicity is formidable, with treatment- related mortality reported in the 30% range. Thus, effective therapy that maintains the patient with CML in CP with minimal toxicity is the goal for treatment of modern therapies. Because the preeminent mutation driving CML is BCr-ABL, therapies targeting BCr-ABL are the logical choice for disease-specific therapy. BCr-ABL inhibitors, such as imatinib, are proof that targeting specific genetic mutations associated with cancer yields a high degree of efficacy with minimal toxicity. OBJECTIVES: This review will outline the evolution of therapy in CML. Preimatinib and imatinib-based treatment strategies, clinical efficacy, and the mechanism of imatinib resistance will be discussed. SUMMARY: The discovery of the Ph and, subsequently, the identification of BCr-ABL revolutionized the treatment of CML. Cytoreductive chemotherapy, such as busulfan and hydroxyurea, was a mainstay of therapy to control white blood cell (wBC) counts; however, it did not modify the progression of the disease to AP and BP. The overall survival with CML ranges from 45 to 58 months in patients treated with cytoreductive therapy only. Treatment was advanced with the introduction of interferon (IFn ) immunotherapy in the 1980s. In some studies, IFn produced a complete hematologic response (CHr) in more than 50% of patients; however, its nonspecific immunostimulatory mechanism also produced severe flu-like symptoms that limited tolerability. Despite the significant toxicity, cost, and inconvenience of injecting IFn thrice weekly, median survival ranged from 60 to 89 months. Allogeneic BMT is the only known curative therapy for CML; however, treatment-related mortality from infection, bleeding, and graft versus host disease, age, and the availability of suitable donors limits its widespread use. Imatinib functions by competing with adenosine triphosphate (ATP) for binding to the BCr-ABL tyrosine kinase. In the absence of ATP, BCr-ABL is not able to activate downstream effector tyrosine kinase molecules that drive wBC proliferation. The International randomized Interferon versus STI571 clinical trial was the first to document the efficacy of imatinib as a first-line therapy for patients in CP. More than 90% of these patients had a CHr. Toxicities associated with this therapy are low. response in patients with advanced CML is less pronounced than in CP and is shorter lived, with less than 30% of patients achieving a CHr. For patients with CML in BP, the only viable therapy is to attempt a temporary reduction in disease burden with a salvage chemotherapy regimen, such as vAC (etoposide, cytarabine, and carboplatin). The goal of this induction chemotherapy is to induce a second remission; then the patient may be considered for allogeneic BMT. The main toxicities seen with imatinib therapy are myelosuppression, edema, and myalgia/arthralgia. In many cases, imatinib dosage can be briefly halted or lowered while the toxicity is managed. Imatinib resistance may develop at any time and inevitably leads to disease progression. Resistance is usually caused by mutations within BCr-ABL, decreasing the affinity of imatinib binding. Next-generation kinase inhibitors are focused on the ability to inhibit these mutated forms of BCr-ABL. CONCLUSIONS: For the majority of patients with CMLin CP, the standard of care is to maintain the patient in CP with imatinib therapy. Clinical trials have been extraordinarily successful, with 5-year survival rates greater than 90%. Allogeneic BMT continues to be an option for those who cannot tolerate imatinib or when CML progresses on imatinib therapy.

OBjeCTIve: This review will outlinethe evolution of therapyinCML.Preimatinib andimatinib-based treatmentstrategies,clinicalefficacy,and the mechanism of imatinib resistance will be discussed.
Imatinib functions by competingwithadenosine triphosphate (ATP)for bindingtothe BCr-ABL tyrosine kinase.Inthe absence of ATP, BCr-ABL is notabletoactivate downstream effector tyrosine kinase moleculesthat drivewBC proliferation.The International randomizedInterferonversus STI571 clinicaltrial wasthe firsttodocument theefficacy of imatinib as a first-line therapyfor patients in CP.Morethan90% of these patients hada CHr. Toxicities associated with this therapyare low. response in patients with advancedCML is less pronouncedthaninCPand is shorterlived, with less than 30%ofpatients achieving aCHr.For patients with CML in BP,the only viabletherapy is to attemptatemporaryreduction in disease burden with asalvage chemotherapyregimen, suchasvAC (etoposide, cytarabine,and carboplatin).The goal of this inductionchemotherapyisto induce asecondremission;thenthe patientmay be consideredfor allogeneic BMT.
OBjeCTIve: This review will outlinethe evolution of therapyinCML.Preimatinib andimatinib-based treatmentstrategies,clinicalefficacy,and t he mechanism of imatinib resistance will be discussed.
Imatinib functions by competingwithadenosine triphosphate (ATP)for bindingtothe BCr-ABL tyrosine kinase.Inthe absence of ATP, BCr-ABL is notabletoactivate downstream effector tyrosine kinase moleculesthat drivewBC proliferation.The International randomizedInterferonversus STI571 clinicaltrial wasthe firsttodocument theefficacy of imatinib as a first-line therapyfor patients in CP.Morethan90% of these patients hada CHr. Toxicities associated with this therapyare low. response in patients with advancedCML is less pronouncedthaninCPand is shorterlived, with less than 30%ofpatients achieving aCHr.For patients with CML in BP,the only viabletherapy is to attemptatemporaryreduction in disease burden with asalvage chemotherapyregimen, suchasvAC (etoposide, cytarabine,and carboplatin).The goal of this inductionchemotherapyisto induce asecondremission;thenthe patientmay be consideredfor allogeneic BMT.
COnCLuSIOn:For themajorityofpatients with CML in CP,the standard of care is to maintain thepatientinCPwithimatinib therapy. Clinicaltrials have been extraordinarilysuccessful, with 5-year survival ratesgreater than 90%. Allogeneic BMTcontinuestobeanoption forthose whocannot tolerate imatinib or when CML progresses on imatinib therapy.

■■ Pre-imatinib Therapies
CytoreductiveTher apy Busulfan wasone of theinitialagentstotreat CML. It hasefficacy in controlling elevated whiteb lood cell (WBC)c ountso vera period of severaly ears.H owever,b usulfant herapyi sn ot without toxicity.Perhapsthe most well-known toxicity is pulmonary fibrosis,commonlytermed"busulfan lung." This toxicity appears to be related to thed urationo fe xposure to thed rug. Patients progressed to AP andBP, with amedian survival of 45 months.

OtherToxicities
Nauseaand vomitingcan be largelya voided by taking imatinib with food.M yalgia anda rthralgiam ay be treated with nonsteroidal anti-inflammatoryd rugs,w itht he caveat thatt he plateletc ount cannot be low. Rash is common.T he patientc an be rechallengedorthe imatinibdose lowered. Novartis will supply, on request, av erys pecifica lgorithm forr estartingt herapy at a lowerd oset ot ry to minimize recurrence of ther ash. Finally, imatinibinhibitscytochrome P450 3A4and thus hasn umerous drug interactions with otherd rugs usingt hisl iverm etabolic pathway.

■■ Imatinib Resistance
Acquired resistance refers to theability of CMLtodevelop resistancetoimatinibovertime. Disease progressiondespite imatinib is inevitablei np atientsw ho acquirethese mutations. The most common causeisthe mutation of BCR-ABLt oaf ormthatisn o longer sensitive to imatinib. This is them ost common form of resistance,a nd numerous mutationsc ausing resistance have been identified andc haracterized.A nother mechanism leading to resistance is gene amplification. Herethe number of BCR-ABL proteins produced exceedsthe ability of imatinibtoinhibit.
The author has served as aconsultantfor AbraxisOncology andfor AmgenInc.